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Sex differences in genetic associations with longevity in Han Chinese: sex-stratified genome-wide association study and polygenic risk score analysis

Author

Listed:
  • Yi Zeng

    (Max Planck Institute for Demographic Research, Rostock, Germany)

  • Huashuai Chen
  • Xiaomin Liu
  • Rui Ye
  • Enjun Xie
  • Zhihua Chen
  • Jiehua Lu
  • Jianxin Li
  • Yaohua Tian
  • Ting Ni
  • Lars Bolund
  • Kenneth C. Land
  • Anatoliy Yashin
  • Angela M. O'Rand
  • Liang Sun
  • Ze Yang
  • Wei Tao
  • Anastasia Gurinovic
  • Claudio Franceschi
  • Jichun Xie
  • Jun Gu
  • Yong Hou
  • Xiao Liu
  • Xun Xu
  • Jean-Marie Robine
  • Joris Deelen
  • Paola Sebastiani
  • P. Eline Slagboom
  • Thomas T. Perls
  • Elizabeth R. Hauser
  • William Gottschalk
  • Qihua Tan

    (Max Planck Institute for Demographic Research, Rostock, Germany)

  • Kaare Christensen
  • Mike Lutz
  • Xiao-Li Tian
  • Huanming Yang
  • Junxia Min
  • Chao Nie
  • James W. Vaupel

    (Max Planck Institute for Demographic Research, Rostock, Germany)

Abstract

Based on sex-stratified genome-wide association study (GWAS) of Han Chinese, 2,178 centenarians and 2,299 middle-aged controls, we identified 11 male- and 12 female-specific independent loci that are significantly associated with longevity (P-5), replicated in independent North and South regions in one sex, but are not significant (P>0.05) in the other sex. We found that the association of rs60210535 at LINC00871 with longevity replicated well between Chinese females (P=4.6x10-5) and U.S. females (P=9.0x10-5), but was not significant in both Chinese and U.S. males (P>0.05). We discovered that 11 male-specific and 34 female-specific pathways are significantly associated with longevity (PFDR) P-5 in one sex, P>0.05 in other sex), 44/58 male/female strong loci (10-5≤P-4 in one sex, P>0.4 or P>0.35 in other sex), and 191/311 male/female moderate loci (10-4≤P-3 in one sex, P>0.75 or P>0.7 in other sex) are jointly and highly associated with longevity exceeding a significance level P10-8 in one sex, but not jointly associated with longevity in the other sex (P>0.05). Our integrated PRS and novel sex-specific genetic relative benefit/loss ratio analyses indicate that females’ genetic constitution favors longevity more than males’. Further interdisciplinary collaborative efforts are warranted, such as replications from other populations, international meta-analyses with much larger sample size, lab tests, and in silico functional validations. Significance Statement: On average, women live significantly longer lives than men but they have lower physical performance and more adverse health outcomes at older ages compared to men: patterns that signify the male-female health-survival paradox (1). Research on sex differences in health and mortality has proliferated, but has yet to achieve a good understanding of the effects of genetic variants on the sex gap in longevity and health. Based on sex-stratified genome-wide association analysis (GWAS) of Han Chinese including centenarians with a sample size 2.7 times as large as other published largest single GWAS on longevity involving centenarians (2), the present study aims to contribute a better understanding of sex differences in genetic associations with longevity.

Suggested Citation

  • Yi Zeng & Huashuai Chen & Xiaomin Liu & Rui Ye & Enjun Xie & Zhihua Chen & Jiehua Lu & Jianxin Li & Yaohua Tian & Ting Ni & Lars Bolund & Kenneth C. Land & Anatoliy Yashin & Angela M. O'Rand & Liang S, 2017. "Sex differences in genetic associations with longevity in Han Chinese: sex-stratified genome-wide association study and polygenic risk score analysis," MPIDR Working Papers WP-2017-004, Max Planck Institute for Demographic Research, Rostock, Germany.
    • Handle: RePEc:dem:wpaper:wp-2017-004
    DOI: 10.4054/MPIDR-WP-2017-004
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    References listed on IDEAS

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    1. Hastie, Nicholas D. & van der Loos, Matthijs J. H. M. & Vitart, Veronique & Völzke, Henry & Wellmann, Jürgen & Yu, Lei & Zhao, Wei & Allik, Jüri & Attia, John R. & Bandinelli, Stefania & Bastardot,, 2013. "GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment," Scholarly Articles 13383543, Harvard University Department of Economics.
    2. Frank Dudbridge, 2013. "Power and Predictive Accuracy of Polygenic Risk Scores," PLOS Genetics, Public Library of Science, vol. 9(3), pages 1-17, March.
    3. Harris, K.M. & Halpern, C.T. & Hussey, J. & Whitsel, E.A. & Killeya-Jones, L. & Tabor, J. & Elder, G. & Hewitt, J. & Shanahan, M. & Williams, R. & Siegler, I. & Smolen, A., 2013. "Social, behavioral, and genetic linkages from adolescence into adulthood," American Journal of Public Health, American Public Health Association, vol. 103(SUPPL.1), pages 25-32.
    4. Herman Oyen & Wilma Nusselder & Carol Jagger & Petra Kolip & Emmanuelle Cambois & Jean-Marie Robine, 2013. "Gender differences in healthy life years within the EU: an exploration of the “health–survival” paradox," International Journal of Public Health, Springer;Swiss School of Public Health (SSPH+), vol. 58(1), pages 143-155, February.
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    JEL classification:

    • J1 - Labor and Demographic Economics - - Demographic Economics
    • Z0 - Other Special Topics - - General

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